Hearing loss is a common communication disorder. Congenital hearing impairment occurs in approximately 1 in 1,000 children born in the United States. See Jain et al., A human recessive neurosensory nonsyndromic hearing impairment locus is a potential homologue of the murine deafness (dn) locus, Human Molecular Genetics 4(12): 2391-2394 (1995); and Scott et al., Refining the DFNB7-DFNB11 deafness locus using intragenic polymorphisms in a novel gene, TMEM2, Gene 246: 265-274 (2000). One to two percent of graduates of neonatal intensive care units also suffer such hearing impairment. See Jain et al. (1995), supra. Nearly 1 in 2 adults have functionally significant hearing loss by the eighth decade of life.
Deafness can be caused by a number of environmental and disease-related factors. In developed countries, however, at least 50% of the cases of deafness are inherited. See Scott et al. (2000), supra. Factors associated with an increased risk for hearing loss include male gender, exposure to aminoglycoside antibiotics, exposure to noise, head trauma, and barotraumas. The majority of cases seem to involve single gene mutations, as there is no additional clinical anomaly, and an autosomal recessive mode of inheritance predominates. Nonsyndromic hereditary hearing impairment (NSHHI) is considered to be highly heterogeneous, and is thought to be caused by a large number of genes.
Vertebrates detect sounds, body accelerations and water movements with the acoustico-lateralis sensory system (Hudspeth et al., Sensitivity, polarity, and conductance change in the response of vertebrate hair cells to controlled mechanical stimuli, Proc. Natl. Acad. Sci. USA 74(6): 2407-2411 (1977)). The primary receptors of this system are neuroepithelial cells termed hair cells. Each of these cells has a “hair bundle” on its apical surface, which is comprised of an elongated microvillus (stereocilium) and, in most cases, a single true cilium (kinocilium). Vibrations, such as from sound waves, stimulate the cells by bending the hair bundles. Bending of the hair bundles leads to the production of a small receptor potential, which excites afferent nerve fibers by chemical or electrical synapses. The exact mechanism of the production of the potential is not yet known, with the existence of conflicting data as to the ions involved in creating the potential (Corey et al., Ionic basis of the receptor potential in a vertebrate hair cell, Nature 281: 675-77 (1979)).
Thus far, linkage studies have been the primary method employed to identify potential loci implicated in hereditary deafness. However, single families suitable in size for conventional linkage analysis are not common. NSHHI also lends itself poorly to subclassification by audiometric criteria. Thus, traditional studies have used consanguineous families from geographically isolated populations to map several different loci which are associated with recessive NSHHI (Jain et al. (1995), supra). In humans certain forms of NSHHI have been found to localize to a region of chromosome 9. See, e.g. Kurima et al., Genetic map localization of DFNA34 and DFNA36, two novel autosomal dominant nonsyndromic deafness loci, ARO Abstracts 24:265 (2001); and Scott et al. (2000), supra. Scott et al. identified a gene in the relevant region of the chromosome; however, it was poorly correlated to hearing loss at the particular locus, as the protein was expressed in a variety of other tissues, such as the heart, brain, spleen, lung, liver, muscle and kidney, and no difference in transcript size or expression level was apparent between normal and deaf mice by Northern blot analysis.
In view of the above, it is an object of the present invention to provide a gene that correlates well with hearing loss as well as the encoded polypeptide and related vectors, host cells, polypeptides, antibodies, antibody-producing cell lines and methods of diagnosing, prognosticating and treating hearing loss. These and other objects and advantages of the present invention, as well as additional inventive features, will be apparent from the description of the invention provided herein.